In mammals, reproductive activity is initiated and maintained by physiological factors associated with nutrition, adiposity, and metabolism; however, little is understood about mechanisms that mediate the integration of metabolism and reproduction. Leptin is a newly discovered satiety hormone and metabolic activator, which has recently been shown to have stimulatory effects on the reproductive system and has been postulated to serve as an important conduit linking the body~s metabolic and reproductive control systems. The overall goal of this research is to understand the cellular and molecular mechanisms of leptin~s action on the neuroendocrine reproductive axis-focusing on 4 hypothalamic regions-the arcuate, dorsomedial, paraventricular, and medial preoptic nuclei. The specific aims are first, to elucidate the role of proopiomelanocortin neurons and the melanocortin type 4 receptor in mediating leptin's effect on reproductive function and to identify their anatomical substrate; second, to examine the functional significance of agouti- related protein (ARP) in mediating leptin~s action in the brain and to trace the cellular pathway of ARP~s action in the hypothalamus. These studies will be performed with laboratory rats and different lines of transgenic mice as the experimental animals. The methods used to accomplish these objectives will include various in vivo pharmacological and endocrine manipulations, hormone assays, single- an double-label in situ hybridization, antisense oligonucleotide blockade of neuropeptide synthesis, neuronal tract tracing, and the creation and analysis of several new lines of mutant/transgenic mice bearing alterations in one or more genes related to leptin's signaling mechanism. Learning more about the mechanisms of leptin's action on the brain may help us to understand the molecular basis of certain disorders of human reproduction (e.g., hypothalamic amenorrhea and infertility linked to metabolic wasting diseases such as diabetes mellitus) and may even provide a rationale for the development of better methods of contraception.